Schizophrenia related gene

ABSTRACT

The present invention provides a new use of the polynucleotide of SEQ ID NO:1, NO:3 and NO:5 or fragments thereof, or the polypeptide encoded from that polynucleotide in the field of the schizophrenia.

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to the gene of the voltage-gated potassium channels Kv3. The present invention also relates to its use in the therapy and/or diagnosis of schizophrenia and to a method of screening for a compound which modulates the expression of the gene or the activity of the voltage-gated-potassium channels.

BACKGROUND OF THE INVENTION

[0002] Schizophrenia is a devastating mental illness that affects 1%,of the world population, the aetiology of which remains elusive. To date, there is a poor understanding of the genes involved. One of the goals of modern antipsychotic drug development is to produce a drug which is more effective in ameliorating the negative symptoms and cognitive deficits characteristic of schizophrenia than existing therapies. Although typical and a typical antipsychotic drugs, such as haloperidol and clozapine respectively, are effective in attenuating the positive symptoms, they are ineffective (haloperidol) or minimally effective (clozapine) against the negative symptoms and cognitive dysfunction associated with the disease (Goldberg, T. E. et al. British Journal of Psychiatry, 1993, 162; 43-48). The development of improved antipsychotic drugs that will have superior action against the negative symptoms and cognitive dysfunction has been severely hampered by the lack of knowledge of which genes are involved and/or associated with schizophrenia. Moreover little is known about the genes, or more specifically any alteration of expression or mutation of the genes in a patient suffering from schizophrenia.

[0003] The Shaw-related family of voltage-gated potassium channels (also known as Kv3 channels) are encoded by four genes (Kv3.1, Kv3.2, Kv3.3 and Kv3.4). The products of these genes have differential expression within the mammalian brain, with Kv3.1 and Kv3.3 channels being predominantly located within a subset of GABAergic interneurons within the brain, namely parvalbumin-containing interneurons (Weiser et al., The Journal of Neuroscience, March 1994, 14(3); 949-972). The function of Kv3.1 and Kv3.3 channels within these interneurons is to allow fast repolarisation of the cells and thus, contributes to the fast-firing phenotype of these neurons (Du et al. The Journal of Neuroscience, Jan. 15, 1996, 16(2); 506-518, Chow et al., The Journal of Neuroscience, Nov. 1, 1999, 19(21); 9332-9345; Erisir et al., The Journal of Neurophysiology, 1999, 82; 2476-2489). Kv3.2 expression is predominantly (90%) within thalamic relay neurons throughout the dorsal thalamus and also in parvalbumin-containing and other GABAergic (Marinotti) interneurons (Moreno et al., The Journal of Neuroscience, August, 1995,15(8); 5486-5501). Parvalbumin expression has been shown to be altered within the prefrontal cortex in schizophrenia (Beasley and Reynolds, Schizophrenia Research, 1997, 24; 349-355), however Kv3.1, Kv3.2 and Kv3.3 expression as not been investigated in this disease state.

[0004] The Shaw-related voltage-gated potassium channels are known to have many names (see below). Present Nomenclature Splice Variants (Alternate names) (Alternate names) Gene Kv3.1 Kv3.1a KCNC1 (KShIIIB; NGK2-KV4) (NGK2; KShIIIB) Kv3.1b (KV4) Kv3.2 Kv3.2a KCNC2 (KShIIIA) (RKShIIIA; KShIIIA.1) Kv3.2b (KShIIIA.3) Kv3.2d (KShIIIA.2) Kv3.3 Kv3.3a KCNC3 (KShIIID) (KShIIID.1) Kv3.3b (KShIIID.2)

[0005] Table adapted from Weiser et al., The Journal of Neuroscience, March 1994, 14(3); 949-972.

[0006] In the present specification, the inventors use the name Kv3.1 for the voltage-gated potassium channel 3.1; Kv3.2 for the voltage-gated potassium channel 3.2 and Kv3.3 for the voltage-gated potassium channel 3.3. Alternate splice variants of each of the Kv3 genes given in the table above), with the splice variants for each gene differing only in their intracellular C-terminal sequence (Coetzee et al., Annals of the New York Academy of Sciences, 1999, 868; 233-285.

[0007] The human Kv3 genes have also been cloned. Kv3.1 α-subunit: GenBank accession number NM_(—)004976; Localization of a highly conserved human potassium channel gene (NGK2-Kv4; KCNCl) to chromosome 11p15. Reid T; Rudy B; Vega-Saenz de Miera E; Lau D; Ward D C and Sen K. (1993). Genomics 15 (2), 405-411. The Kv3.1a α-subunit displays ˜99% sequence identity to the rat sequence, and there is >90% sequence identity between rat and mouse sequences. Kv3.2: GenBank accession number AY118169. Kv3.3:GenBank accession number NM_(—)004977; Genomic organization, nucleotide sequence and cellular distribution of a Shaw-related potassium channel gene, Kv3.3, and mapping of Kv3.3 and Kv3.4 to human chromosomes 19 and 1. Ghanshani et al., Genomics 12(2) 1992; 190-196)

[0008] Chronic treatment with phencyclidine (hereinafter PCP) in the rat provides an animal model of schizophrenia with superior face, construct and predictive validity (WO01/75440). It has been shown to mimic metabolic changes (metabolic hypofunction in the prefrontal cortex, thalamus and auditory structures) that are observed in schizophrenic patients, that can be correlated to both positive and negative symptomology and cognitive deficits associated with the disease, and also neurochemical changes observed in postmortem tissue from schizophrenic patients such as decreased parvalbumin expression and decreased 5HT2A binding. Parvalbumin mRNA was selectively decreased within certain brain regions in the chronic PCP rat model of schizophrenia, the prelimbic region of the prefrontal cortex and the reticular nucleus of the thalamus and this effect was modulated by chronic antipsychotic treatment. Due to the high degree of co-localization between parvalbumin and the Kv3.1 and Kv3.3 channels, the aim was to determine whether Kv3.1 α-subunit expression is similarly altered by the same chronic PCP rat model of schizophrenia. Also, due to the localization of Kv3.2 channels in thalamic relay neurons and GABAergic interneurons, it was also of interest whether Kv3.2 mRNA expression was also altered by the chronic PCP rat model of schizophrenia.

SUMMARY OF THE INVENTION

[0009] The present inventors have found that the Kv3.1 α-subunit ene, or a nucleotide having SEQ ID NO:1; the Kv3.2 gene, or nucleotide having SEQ ID NO:3; and Kv3.3 gene, or a nucleotide having SEQ ID NO:5 show, altered expression in the brain of the chronic PCP rat model of schizophrenia, and also found that the nucleotides and the protein that these nucleotides encodes are useful for the diagnosis or treatment of schizophrenia. The present invention also provides a method of screening a compound that regulates expression and activity of this nucleotide and/or protein. Accordingly, the present invention provides the following.

[0010] (1) A method for diagnosing schizophrenia, which comprises use of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5, a fragment thereof, and a polynucleotide having a sequence complementary to such sequence, as an index of schizophrenia.

[0011] (2) The method of the above-mentioned (1), wherein the at least one kind of polynucleotide is selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5 and a polynucleotide having a sequence complementary to such sequence.

[0012] (3) The method of the above-mentioned (1), wherein the at least one kind of polynucleotide is a polynucleotide having SEQ ID NO:1.

[0013] (4) A method for diagnosing schizophrenia, which comprises use of at least one kind of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3, a polypeptide encoded by the polynucleotide of SEQ ID NO:5, and a fragment thereof, as an index of schizophrenia.

[0014] (5) The method of the above-mentioned (4), wherein the at least one kind of polypeptide is selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3 and a polypeptide encoded by the polynucleotide of SEQ ID NO:5.

[0015] (6) The method of the above-mentioned (4), wherein the at least one kind of polypeptide is a polypeptide encoded by the polynucleotide of SEQ ID NO:1.

[0016] (7) A method for identifying a compound modulating the activity of Kv3 channels, which comprises analyzing an expression of Kv3 channel using at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5, a fragment thereof and a polynucleotide having a sequence complementary 5 to such sequence.

[0017] (8) The method of the above-mentioned (7), wherein the expression of Kv3 channel is analyzed using at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5 and a polynucleotide having a sequence complementary to such sequence.

[0018] (9) The method of the above-mentioned (7), wherein the expression of Kv3 channel is analyzed using a polynucleotide having SEQ ID NO:1.

[0019] (10) A method for identifying a compound modulating the activity of Kv3 channels, which comprises analyzing an expression of Kv3 channel using at least one kind of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3, a polypeptide encoded by the polynucleotide of SEQ ID NO:5, and a fragment thereof.

[0020] (11) The method of the above-mentioned (10), wherein the expression of Kv3 channels is analyzed using at least one kind of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3, and a polypeptide encoded by the polynucleotide of SEQ ID NO:5.

[0021] (12) The method of the above-mentioned (10), wherein the expression of Kv3 channel is analyzed using a polypeptide encoded by the polynucleotide of SEQ ID NO:1.

[0022] (13) A method for screening a compound regulating the expression of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, which comprises the steps of

[0023] (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide, which is at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5 and a fragment thereof, and whose expression is desired to be controlled;

[0024] (b) detecting the expression of polypeptide encoded by the polynucleotide in the cell; and

[0025] (c) determining a compound promoting or suppressing the expression of the polypeptide as compared to a control (administration of vehicle alone).

[0026] (14) A method for screening a compound regulating the, expression of a polynucleotide having SEQ ID NO:1, which comprises the steps of:

[0027] (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of a polynucleotide having SEQ ID NO:1);

[0028] (b) detecting the expression of polypeptide encoded by the polynucleotide in the cell; and

[0029] (c) determining a compound promoting or suppressing the expression of the polypeptide as compared to a control (administration of vehicle alone).

[0030] (15) A method for screening a compound regulating the expression of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, which comprises the steps of:

[0031] (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide, which is at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, and a polynucleotide having SEQ ID NO:5, and whose expression is desired to be controlled);

[0032] (b) detecting the expression of polynucleotide in the cell; and

[0033] (c) determining a compound promoting or suppressing the expression of the polynucleotide as compared to a control (administration of vehicle alone).

[0034] (16) A method for screening a compound regulating the expression of a polynucleotide having SEQ ID NO:1, which comprises the steps of:

[0035] (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide having SEQ ID NO:1);

[0036] (b) detecting the expression of polynucleotide in the cell; and

[0037] (c) determining a compound promoting or suppressing the expression of the polynucleotide as compared to a control (administration of vehicle alone).

BRIEF DESCRIPTION OF THE DRAWING

[0038]FIG. 1 shows a chronic intermittent PCP treatment regime (YRING Model).

DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention relates to methods for prognostic and/or diagnostic evaluation of schizophrenia and/or for the identification of subjects who are predisposed to schizophrenia, for example by examination of allelic variation of the gene identified herein in an individual or by determination of the expression of the gene in an individual. Furthermore, the invention provides methods for evaluating the efficacy of drugs for such disorders, and monitoring the progress of patient symptoms involved in clinical trials for the treatment of such disorders.

[0040] The invention further provides methods for the identification of compounds that modulate the expression of the Kv3 genes and/or the activity of the Kv3.1, Kv3.2 or Kv3.3 channels. Such identified compounds may be used in the treatment of schizophrenia.

[0041] By the “regulate” is meant here the action to promote or suppress the expression of the gene, which varies according to the desired effect. In consideration of the application to Schizophrenia, however, screening of a compound that increases the level of expression of Kv3.1 α-subunit gene is preferable and a compound that decreases the level of the Kv3.2 and Kv3.3 gene is preferable.

[0042] In the present invention, the “polynucleotide having a sequence complementary” means a sequence complementary to a target sequence to the extent that hybridization under stringent conditions occurs, wherein stringency can be appropriately determined according to the method employed.

[0043] In the present invention, the “fragment” means a poly(oligo)nucleotide or a poly(oligo)peptide obtained by fragmentation of polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5, a polypeptide encoded by the polynucleotide of SEQ ID NO:1 (i.e., SEQ ID NO:2), a polypeptide encoded by the polynucleotide of SEQ ID NO:3 (i.e., SEQ ID NO:4) or a polypeptide encoded by the polynucleotide of SEQ ID NO:5 (i.e., SEQ ID NO:6) to the extent that affords reproduction of characteristic mode of expression found in the pharmacology of schizophrenia. For example, the fragment may be any as long as the expression of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5, a polypeptide having SEQ ID NO:2, a polypeptide having SEQ ID NO:4 and a polypeptide having SEQ ID NO:6 in patients with schizophrenia can be observed and the size thereof is not particularly limited.

[0044] The “at least one kind of polynucleotide” of the “at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5, a fragment thereof, and a polynucleotide having a sequence complementary to the sequence” intends, in addition to each polynucleotide, two kinds of polynucleotides selected from the group, or 3 kinds of polynucleotides selected from the group and the like. It means, for example, one kind of, two kinds of and all three kinds of polynucleotides selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5. Likewise, the “at least one kind of polypeptide” of the “at least one kind of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3, a polypeptide encoded by the polynucleotide of SEQ ID NO:5, a fragment thereof, and a polypeptide having a sequence complementary to the sequence” intends, in addition to each polypeptide, two kinds of polypeptides selected from the group, or 3 kinds of polypeptides selected from the group and the like. It means, for example, one kind of, two kinds of and all three kinds of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3 and a polypeptide encoded by the polynucleotide of SEQ ID NO:5. Preferably, it is a polynucleotide having SEQ ID NO:1 or polypeptide encoded by the polynucleotide of SEQ ID NO:1.

[0045] The present invention provides a method for screening a compound regulating the expression of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, which comprises the steps of

[0046] (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide, which is at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5 and a fragment thereof and whose expression is desired to be controlled);

[0047] (b) detecting the expression of polypeptide encoded by the polynucleotide in the cell; and

[0048] (c) determining a compound promoting or suppressing the expression of the polypeptide as compared to a control (administration of vehicle alone).

[0049] In the above-mentioned screening method, the “test compound” is free of any particular limitation as long as it is the object compound for which capability of regulating the expression of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, preferably a polynucleotide having SEQ ID NO:1 is desired to be determined, and it may be a novel or known compound. A combination drug can be the object compound. More specifically, chronic PCP administration that affects the expression of the Kv3 mRNAs is combined with administration of the test compound. By analyzing the metabolic and neurochemical state induced by the chronic PCP administration and changes in the expression of the Kv3 mRNAs, the effect of the test compound can be investigated.

[0050] In the above-mentioned screening method, the cell is free of any particular limitation as long as it expresses at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, preferably a polynucleotide having SEQ ID NO:1. It may be naturally occurring or processed to express said polynucleotide by genetic recombination.

[0051] For detection of intracellular expression of polypeptide and comparison with control, the methods and techniques generally used in this field can be used and those of ordinary skill in the art can modify them suitably. Specific examples thereof include western blotting capable of detection at a protein level.

[0052] Moreover, the method for screening a compound regulating the expression of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, may comprise the steps of

[0053] (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide, which is at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5 and whose expression is desired to be controlled);

[0054] (b) detecting the expression of polynucleotide in the cell; and

[0055] (c) determining a compound promoting or suppressing the expression of the polynucleotide as compared to a control (administration of vehicle alone).

[0056] Each term is as mentioned above, and for detection of intracellular expression of polynucleotide and comparison with control, the methods and techniques generally used in this field can be used and those of ordinary skill in the art can modify them suitably. Specific examples thereof include northern blotting capable of detection at an mRNA level.

[0057] The information obtained through the screening method and diagnostic method of the present invention (hereinafter to be generally referred to as characterization) can suggest relevant methods for the treatment or control of schizophrenia. For example, relevant treatment can include a regulation of gene expression and/or a modulation of gene product activity. Characterization procedures such as those described herein can indicate whether such regulation/modulation should be positive or negative. As used herein, “positive regulation/modulation” refers to an increase in gene expression and/or the activity of gene product of interest. “Negative regulation/modulation”, as used herein, refers to a decrease in gene expression and/or activity.

[0058] In vitro systems can be designed to identify compounds capable of binding with said Kv3 genes products of the invention.

[0059] SEQ ID NO:1 shows the nucleotide sequence of the rat Kv3.1 α-subunit gene of the present invention, SEQ ID NO:3 shows the nucleotide sequence of the rat Kv3.2 gene of the present invention and SEQ ID NO:5 shows the nucleotide sequence of the rat Kv3.3 gene of the present invention, which were observed to be differentially expressed in the brain in the chronic PCP rat model of schizophrenia.

[0060] SEQ ID NO:2 shows the amino acid sequence of the rat Kv3.1 α-subunit of the present invention, SEQ ID NO:4 shows the amino acid sequence of the rat Kv3.2 of the present invention and SEQ ID NO:6 shows the amino acid sequence of the rat Kv3.3 of the present invention which were observed to be differentially expressed in the brain in the chronic PCP rat model of schizophrenia.

[0061] SEQ ID NO:7 shows the oligonucleotide (45mer) used for in situ hybridization for the Kv3.1 α-subunit mRNA; SEQ ID NO:8 shows the oligonucleotide (45mer) used for in situ hybridization for the Kv3.2 mRNA; SEQ ID NO:9 shows the oligonucleotide (45mer) used for in situ hybridization for the Kv3.3 mRNA.

[0062] The present invention is explained in more detail in the following by way of Experiments, which are not to be construed as limitative.

[0063] In this specification, Y-931 means 8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[l]benzothieno[2,3-b][1,5]benzo-diazepine monomaleate, which is known as an a typical antipsychotic drug (WO99/11647).

[0064] Experiment

[0065] Method

[0066] Experiment 1

[0067] Male Sprague-Dawley rats, weighing 224-260 g at the beginning of the study, were randomly assigned to one of ten treatment groups as follows: vehicle (0.02N HCl in saline)-vehicle (polyethyleneglycol); PCP-vehicle; PCP-Y-931 0.3 mg/kg/day; PCP-Y-931 1 mg/kg/day; PCP-Y-931 3 mg/kg/day; PCP-Y-931 10 mg/kg/day; PCP-olanzapine 0.3 mg/kg/day; PCP-olanzapine 1 mg/kg/day; PCP-olanzapine 3 mg/kg/day; PCP-olanzapine 10 mg/kg/day. The dose of PCP used was 2.24 mg/kg (free base equivalent, equal to 2.58 mg/kg PCP.HCl) and PCP was administered according to the chronic PCP rat model of schizophrenia (WO01/75440). Briefly, i.p. injections of PCP (2.24 mg/kg) or saline (1 ml/kg) were administered once daily on days 1-5, 8, 10, 12, 15, 17, 19, 22, 24, 26. Osmotic minipumps (2ML4 (28 day), Alzet) were implanted subcutaneously on day 8 prior to PCP injection to deliver doses of antipsychotics or vehicle detailed above for 21 days of drug treatment. The osmotic minipumps were primed in vitro for 24 hours in order to ensure pumping started immediately upon implantation.

[0068] 29 days after the first PCP injection, the animals were sacrificed, the brains removed and stored at −70° C. Osmotic minipumps were also removed and the dose administered was verified. The brains were sectioned at −20° C. using a cryostat (Leica, CM1850), with 14 μm coronal sections being thaw-mounted onto silanized slides (Dako, Japan) from the following bregma levels according to the Rat Brain Atlas, Paxinos and Watson (2000): 3.22 mm; 1.6 mm, −1.80 mm and −4.8 mm. The sections were then stored at −80° C. over silica gel until required. The oligonucleotide (45mer) used for in situ hybridization for the Kv3.1 α-subunit mRNA was 5′-ATAGTCGAAGTGGCTGTGGGCGTCCGGCTCCGCCAGCCAGGCAAG-3′ (SEQ ID NO:7) complementary to bases 1261-1305 of the rat Kv3.1 α-subunit (GenBank Accession Number NM_(—)012856; Luneau et al., Proc. Natl. Acad. Sci. USA. 1991, 88; 3932-3936). This probe sequence recognizes both alternate splice variants (Kv3.1a and Kv3.1b) of the Kv3.1 channel. The probe was 3′ end-labeled with terminal deoxyribonucleotidyl transferase (Boehringer Mannheim) and with the isotope 5-α- ³⁵S-dATP (Amersham, specific activity >1000 Ci/mmol) and incubated at 37° C. for one hour. The reaction was terminated by addition of 40 μl diethyl pyrocarbonate (DEPC)-treated water. The probe was purified using the QIAquick nucleotide removal kit (Qiagen). The extent of probe labeling was assessed using scintillation counting, and probes labeled from 100,000 to 300,000 d.p.m. μl⁻¹ were used for in situ hybridization. On the day of the in situ hybridization experiment the sections were fixed in 4% paraformaldehyde-0.1M phosphate buffer for 30 mins at 4° C., rinsed twice for 5 mins in 0.1M phosphate buffer saline (PBS), acetylated with 0.25% acetic anhydride in 0.1M triethanolamine for 10 mins, rinsed twice for 5 mins in 2×SSC (0.15M NaCl, 15 mM sodium citrate), dehydrated and delipidated through a graded series of ethanol and chloroform. The sections were then air dried and then hybridized overnight at 42° C. with 0.2-1×10⁻⁶ d.p.m. of the labeled probe in 100 μl of hybridization solution (Hybrisol 1, Intergen) containing 0.1M dithiothreitol. After hybridization, the sections were washed twice for 10 secs in 1×SSC at 55° C., four times for 15 mins in 1×SSC at 55° C., for 1 hour in 1×SSC at room temperature and twice in water for 5 mins. The sections were then dipped successively in 60%, 80%, 90%, 95% and 100% ethanol and air dried. The sections were exposed to BAS 5000 image plates and developed after 7 days. Kv3.1 α-subunit mRNA expression was quantified using a computer-based densitometry system (MCID 5, Canada). Statistical analysis of the data was performed using a students t-test (vehicle-vehicle vs PCP-vehicle) followed by Dunnett's Method (PCP-vehicle vs PCP-antipsychotics). Statistical significance was defined as p<0.05.

[0069] Experiment 2

[0070] In a second experiment using different method for in situ hybridisation, the effect of chronic PCP treatment on Kv3.1, Kv3.2 and Kv3.3 mRNA were examined. 20 male hooded Long Evans rats (250-300 g at the beginning of the study, Harlan UK) were randomly assigned to either vehicle (saline, n=10) or PCP (2.58 mg/kg PCP.HCl, n=10) treatment groups. Animals were treated according to the YRING model (FIG. 1) and killed by cervical dislocation 72 hours after the last exposure to PCP. The brains were stored at −70° C. until required.

[0071] In Situ Hybridisation

[0072] 20 μm coronal sections were cut on a cryostat at −20° C. and collected onto poly-L-lysine coated slides. The sections were fixed, dehydrated and stored under ethanol at 4° C. until required. 45mer oligonucleotide probes designed against rat mRNA for parvalbumin (GeneBank Accession number NM_(—)022499, bases 223-267), Kv3.1 (GeneBank Accession number NM_(—)012856, bases 1261-1305; SEQ ID NO: 7), Kv3.2 (GeneBank Accession number NM_(—)139217, bases 1021-1065; SEQ ID NO: 8) and Kv3.3 (GeneBank Accession number NM 053997, bases 241-285; SEQ ID 30 NO: 9) were 3′ end-labeled with terminal deoxyribonucleotidyl transferase and ³⁵Sd-ATP. On the day of in situ hybridization, the sections from the chronic study were allowed to dry at room temperature then hybridized with the appropriate probe overnight at 42° C. The sections were then washed, dehydrated and air-dried before being exposed to x-ray film for 7-10 days.

[0073] The quantification of mRNA expression was carried out using computer-based densitometry (MCID 5). Bilateral relative optical density measurements were taken from duplicate sections from each animal (n=8-10 per treatment group for the chronic study). The results were analyzed using individual t-tests for each brain region. Statistical significance was defined as p<0.05, again after correction for multiple comparisons using the sequential Bonferroni correction factor.

[0074] Results

[0075] Experiment 1

[0076] Table 1 shows the effect of chronic PCP and antipsychotic treatment on Kv3.1 α-subunit mRNA expression. Chronic PCP treatment selectively decreased Kv3.1 α-subunit mRNA expression within the prelimbic region of the prefrontal cortex (PrL, −31%), the dorsal part of the reticular nucleus of the thalamus (dRt, −15%) and the dorsolateral striatum (DLStr, −16%). Within the PrL, both Y-931 and olanzapine, at all doses administered, significantly reversed the PCP-induced decrease back to control levels. However, within the dRt and the DLStr, neither Y-931 nor olanzapine significantly modulated the PCP-induced effect.

[0077] Compared to PCP-vehicle, PCP-olanzapine treatment (1 mg/kg/day, only) produced a significant decrease in Kv3.1 α-subunit mRNA expression within the granule cell layer of the dentate gyrus (DGgcl) and a significant increase in Kv3.1 α-subunit mRNA expression within the ventromedial striatum (VMStr) (0.3 & 3 mg/kg/day olanzapine, only).

[0078] Experiment 2

[0079] Table 2 shows the levels of Kv3.1 mRNA expression within the rat brain after chronic intermittent treatment according to the YRING model. Very selective changes in Kv3.1 mRNA expression were observed after chronic intermittent exposure to PCP. A significant decrease in Kv3.1 mRNA expression was observed within the prelimbic cortex (−23%) and within the ventral part of the reticular thalamic nucleus (−19%). No other changes were observed in any other regions.

[0080] Table 3 shows the levels of Kv3.2 mRNA expression within the rat brain after chronic intermittent treatment according to the YRING model. A significant increase in Kv3.2 mRNA expression was observed within the prelimbic cortex (+16%) 1 and the primary motor cortex (+13%). A small but significant decrease in Kv3.2 mRNA expression was also observed within the anteromedial thalamic nucleus (−9%). No significant changes were observed after chronic intermittent PCP treatment within any other regions.

[0081] Table 3 shows the levels of Kv3.3 mRNA expression within the rat brain after chronic intermittent treatment according to the YRING model. Within cortical regions, an increase in Kv3.3 mRNA expression after chronic intermittent exposure to PCP was observed within the prelimbic cortex (+18%) and the ventral orbital cortex (+14%). A significant increase in Kv3.3 mRNA expression was also observed within the anterodorsal thalamic nucleus (+21%) and the ventral part of the reticular thalamic nucleus (+33%). No other changes were observed in any other regions. TABLE 1 PCP-Y-931 PCP-Olanzapine 0.3 1 3 10 0.3 1 3 10 Region Veh-Veh PCP-Veh mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day PrL 14.22 ± 0.21  9.83 ± 12.76 ± 12.17 ± 12.93 ± 12.55 ± 12.50 ± 12.78 ± 13.18 ± 12.66 ±  0.23**  0.62††  0.85†  0.33††  0.67†  0.92††  0.54††  0.43††  0.49†† IL 12.30 ± 0.58 12.28 ± 11.64 ± 0.40 11.33 ± 0.60 12.91 ± 0.38 11.55 ± 0.45 12.00 ± 0.65 11.27 ± 1.08 11.40 ± 0.41 12.15 ± 0.62  0.82 M1 16.68 ± 1.06 15.88 ± 15.33 ± 0.38 14.81 ± 0.80 17.01 ± 0.75 16.51 ± 0.67 15.83 ± 0.69 16.17 ± 1.27 16.17 ± 0.79 16.27 ± 0.37  1.53 M2 14.49 ± 0.65 14.38 ± 13.23 ± 0.29 13.10 ± 0.57 14.25 ± 0.81 13.04 ± 0.53 13.72 ± 0.78 12.57 ± 0.94 14.48 ± 0.90 13.14 ± 0.99  0.89 VO 18.42 ± 0.99 19.85 ± 19.12 ± 0.74 17.81 ± 1.08 19.32 ± 0.63 18.51 ± 1.08 19.03 ± 1.00 18.35 ± 1.04 18.96 ± 0.86 19.88 ± 0.58  0.85 IO 16.05 ± 0.96 16.48 ± 17.52 ± 0.95 15.49 ± 0.30 17.52 ± 0.36 15.30 ± 0.62 15.50 ± 0.51 16.18 ± 0.32 16.83 ± 0.79 17.74 ± 0.37  0.69 ACg 14.97 ± 0.84 15.01 ± 15.36 ± 0.29 15.10 ± 0.92 15.40 ± 0.83 14.82 ± 0.74 15.83 ± 0.73 14.83 ± 1.00 16.31 ± 0.40 15.03 ± 0.72  0.54 Pir 37.64 ± 1.18 40.65 ± 38.95 ± 2.38 43.16 ± 2.76 38.15 ± 3.31 41.69 ± 1.90 37.73 ± 1.18 36.82 ± 0.51 43.78 ± 1.20 40.66 ± 2.21  1.64 RSg 18.63 ± 1.60 20.38 ± 20.89 ± 0.95 19.99 ± 0.59 20.73 ± 1.22 19.48 ± 0.64 19.48 ± 0.72 19.43 ± 1.20 20.96 ± 1.08 19.59 ± 0.92  1.32 RSa 15.81 ± 1.42 17.96 ± 19.22 ± 1.40 18.90 ± 1.03 17.36 ± 1.55 18.04 ± 0.87 16.53 ± 1.13 16.92 ± 0.74 18.21 ± 1.15 18.77 ± 1.07  1.43 Au1 16.42 ± 1.46 18.08 ± 17.02 ± 1.26 18.48 ± 1.36 16.76 ± 0.32 17.98 ± 0.68 18.60 ± 1.75 18.68 ± 0.80 17.42 ± 1.46 16.91 ± 0.86  1.04 DGgd 34.86 ± 2.50 38.63 ± 38.38 ± 1.53 39.21 ± 1.75 36.93 ± 2.53 36.11 ± 2.06 35.22 ± 1.16 33.04 ± 36.51 ± 1.07 38.16 ± 1.10  1.47  2.15† CA1pd 16.98 ± 1.79 15.90 ± 16.80 ± 1.23 18.34 ± 0.91 16.47 ± 0.98 19.18 ± 2.03 19.98 ± 1.59 19.14 ± 2.06 18.37 ± 1.54 20.15 ± 1.22  0.97 CA2pd 21.38 ± 1.27 18.61 ± 24.07 ± 1.74 20.07 ± 1.71 21.47 ± 2.23 22.31 ± 1.57 21.36 ± 2.52 17.72 ± 1.86 24.21 ± 1.23 20.59 ± 1.35  1.29 CA3pd 31.46 ± 1.68 32.94 ± 34.10 ± 1.52 33.99 ± 3.29 34.72 ± 1.24 33.90 ± 2.52 33.71 ± 3.48 30.50 ± 1.94 33.46 ± 2.04 32.81 ± 1.82  2.69 dRt 56.97 ± 2.24 48.80 ± 54.94 ± 1.99 51.68 ± 2.34 53.38 ± 2.99 54.81 ± 1.90 50.99 ± 2.22 50.92 ± 3.80 52.87 ± 1.95 52.42 ± 1.19  2.72* vRt 46.12 ± 3.47 45.07 ± 46.91 ± 2.73 47.18 ± 2.10 52.57 ± 2.00 49.70 ± 2.76 54.57 ± 3.12 46.70 ± 3.99 42.97 ± 2.22 53.69 ± 2.07  2.26 DLStr  6.98 ± 0.20  5.87 ±  6.55 ± 0.53  5.99 ± 0.96  7.13 ± 0.70  7.46 ± 0.86  6.87 ± 0.38  6.99 ± 0.43  6.84 ± 0.42  6.70 ± 0.59  0.44* VMStr  6.80 ± 0.20  6.15 ±  6.75 ± 0.50  7.18 ± 0.71  7.69 ± 0.35  7.23 ± 0.26  7.33 ±  6.88 ± 0.46  7.52 ±  5.99 ± 0.28  0.23  0.24†  0.16†† SN 12.47 ± 0.55 12.82 ± 11.66 ± 0.91 12.98 ± 1.12 13.04 ± 1.29 15.34 ± 1.58 13.27 ± 1.21 13.98 ± 0.96 13.09 ± 0.44 12.54 ± 0.68  1.09 AcbC 8.57 ± 0.53 8.48 ± 7.65 ± 0.40 8.40 ± 0.63 8.44 ± 0.43 8.42 ± 0.53 8.59 ± 0.58 8.12 ± 0.67 8.55 ± 0.25 8.27 ± 0.31  0.51 AcbS 10.01 ± 0.67 10.62 ± 10.24 ± 0.64 11.55 ± 0.50 11.11 ± 0.27 11.26 ± 0.67 11.42 ± 0.73 10.43 ± 0.56 11.62 ± 0.84 11.95 ± 1.02  0.61 MM 25.86 ± 1.87 24.34 ± 25.02 ± 2.54 24.82 ± 0.93 20.92 ± 0.93 28.12 ± 1.89 25.36 ± 2.25 25.76 ± 1.27 25.24 ± 2.32 4.69 ± 2.24  2.53 MG 25.23 ± 1.50 26.93 ± 26.82 ± 1.55 26.36 ± 0.95 26.75 ± 2.02 27.36 ± 1.86 26.64 ± 2.22 25.50 ± 1.46 24.56 ± 1.41 25.78 ± 0.77  1.46

[0082] TABLE 2 Kv3.1 mRNA expression in rat brain after chronic intermittent exposure to vehicle or PCP (YRING model). Relative Optical Density (ROD) PCP Brain Region Vehicle (2.58 mg/kg) % Control Cortical Regions PrL 0.112 ± 0.002 0.086 ± 0.004**  77 ± 4** IL 0.103 ± 0.003 0.098 ± 0.004  95 ± 4 vO 0.122 ± 0.003 0.122 ± 0.004 100 ± 3 lO 0.101 ± 0.003 0.092 ± 0.003  91 ± 3 M1 0.123 ± 0.004 0.120 ± 0.004  98 ± 3 M2 0.116 ± 0.002 0.106 ± 0.004  91 ± 3 ACg 0.126 ± 0.006 0.116 ± 0.004  92 ± 3 Pir 0.263 ± 0.006 0.243 ± 0.014  92 ± 5 RSG 0.148 ± 0.006 0.153 ± 0.008 103 ± 5 RSA 0.127 ± 0.005 0.135 ± 0.006 106 ± 5 Au1 0.138 ± 0.008 0.137 ± 0.009  99 ± 6 LEnt 0.096 ± 0.008 0.093 ± 0.005  97 ± 5 Thalamus AD 0.215 ± 0.006 0.216 ± 0.006 100 ± 3 dRt 0.274 ± 0.007 0.258 ± 0.013  94 ± 5 vRt 0.275 ± 0.010 0.224 ± 0.008**  81 ± 3** Hippocampus DG gcl 0.244 ± 0.005 0.239 ± 0.012  98 ± 5 CA1pcl 0.128 ± 0.006 0.122 ± 0.007  95 ± 5 CA2pcl 0.156 ± 0.009 0.156 ± 0.010 100 ± 6 CA3pcl 0.202 ± 0.007 0.203 ± 0.009 100 ± 4

[0083] TABLE 3 Kv3.2 mRNA expression in rat brain after chronic intermittent exposure to vehicle or PCP (YRING model). Relative Optical Density (ROD) PCP Brain Region Vehicle (2.58 mg/kg) % Control Cortical Regions PrL 0.079 ± 0.002 0.092 ± 0.003* 116 ± 4 IL 0.079 ± 0.003 0.083 ± 0.002 105 ± 2 vO 0.074 ± 0.002 0.078 ± 0.003 105 ± 4 lO 0.069 ± 0.002 0.073 ± 0.002 106 ± 3 M1 0.067 ± 0.002 0.076 ± 0.003* 113 ± 4 M2 0.076 ± 0.003 0.079 ± 0.004 104 ± 5 ACg 0.078 ± 0.002 0.075 ± 0.002  96 ± 2 Pir 0.140 ± 0.005 0.138 ± 0.006 98 ± 4 RSG 0.065 ± 0.004 0.069 ± 0.002 106 ± 3 RSA 0.070 ± 0.002 0.065 ± 0.002  93 ± 3 Au1 0.070 ± 0.002 0.068 ± 0.003  97 ± 4 LEnt 0.051 ± 0.003 0.048 ± 0.002  94 ± 4 Thalamus AV 0.275 ± 0.006 0.269 ± 0.005  98 ± 2 AM 0.248 ± 0.005 0.227 ± 0.006*  91 ± 2 MD 0.211 ± 0.008 0.187 ± 0.010  89 ± 5 VA 0.240 ± 0.008 0.223 ± 0.006  93 ± 2 VM 0.206 ± 0.009 0.201 ± 0.005  98 ± 2 VL 0.211 ± 0.010 0.208 ± 0.004  98 ± 2 LDVL 0.194 ± 0.009 0.197 ± 0.004 102 ± 2 LDDM 0.203 ± 0.008 0.205 ± 0.007 101 ± 3 VPL 0.175 ± 0.007 0.180 ± 0.005 103 ± 3 MGD 0.175 ± 0.006 0.164 ± 0.006  94 ± 3 MGV 0.193 ± 0.007 0.185 ± 0.003  96 ± 2 DLG 0.195 ± 0.012 0.222 ± 0.007 114 ± 4 Hippocampus DG gcl 0.097 ± 0.004 0.095 ± 0.007  98 ± 7 CA1pcl 0.069 ± 0.004 0.075 ± 0.004 109 ± 6 CA2pcl 0.080 ± 0.002 0.082 ± 0.003 102 ± 4 CA3pcl 0.142 ± 0.005 0.134 ± 0.005  94 ± 4

[0084] TABLE 4 Kv3.3 mRNA expression in rat brain after chronic intermittent exposure to vehicle or PCP (YRING model). Relative Optical Density (ROD) PCP Brain Region Vehicle (2.58 mg/kg) % Control Cortical Regions PrL 0.057 ± 0.002 0.067 ± 0.003* 118 ± 5 IL 0.053 ± 0.002 0.059 ± 0.002 111 ± 4 vO 0.073 ± 0.003 0.083 ± 0.003* 114 ± 4 lO 0.053 ± 0.002 0.058 ± 0.002 109 ± 4 M1 0.085 ± 0.003 0.093 ± 0.002 109 ± 2 M2 0.073 ± 0.002 0.075 ± 0.003 103 ± 4 ACg 0.068 ± 0.003 0.069 ± 0.003 101 ± 4 Pir 0.111 ± 0.005 0.115 ± 0.006 104 ± 5 RSG 0.087 ± 0.004 0.092 ± 0.004 106 ± 4 RSA 0.066 ± 0.003 0.067 ± 0.003 102 ± 4 Au1 0.075 ± 0.002 0.076 ± 0.003 101 ± 4 LEnt 0.042 ± 0.002 0.047 ± 0.002 112 ± 5 Thalamus AD 0.173 ± 0.009 0.209 ± 0.001* 121 ± 1 dRt 0.186 ± 0.001 0.198 ± 0.006 106 ± 3 vRt 0.121 ± 0.010 0.161 ± 0.007* 133 ± 6 Hippocampus DG gcl 0.254 ± 0.009 0.275 ± 0.011 108 ± 4 CA1 pcl 0.144 ± 0.006 0.146 ± 0.006 101 ± 4 CA2 pcl 0.149 ± 0.005 0.148 ± 0.007  99 ± 5 CA3 pcl 0.204 ± 0.006 0.210 ± 0.006 103 ± 3

[0085] Abbreviations:

[0086] PrL, prelimbic cortex;

[0087] IL, infralimbic cortex;

[0088] M1, primary motor cortex;

[0089] M2, secondary motor cortex;

[0090] vO, ventral orbital cortex;

[0091] lO, lateral orbital cortex;

[0092] Acg, anterior cingulate cortex;

[0093] Pir, piriform cortex;

[0094] RSg, granular retrosplenial cortex;

[0095] Rsa, agranular retrosplenial cortex;

[0096] Aul, primary auditory cortex;

[0097] LEnt, lateral entorhinal cortex;

[0098] DGgcl, granule cell layer of the dentate gyrus;

[0099] CA1-CA3 pcl, pyramidal cell layer of the CA1-CA3 fields of

[0100] the hippocampus;

[0101] AD, anterodorsal nucleus of the thalamus;

[0102] AV, anteroventral nucleus of the thalamus;

[0103] AM, ateromedial nucleus of the thalamus;

[0104] MD, mediodorsal nucleus of the thalamus;

[0105] VA, ventral anterior nucleus of the thalamus;

[0106] VM, ventral medial nucleus of the thalamus;

[0107] VL, ventral lateral nucleus of the thalamus;

[0108] LDVL, laterodorsal thalamic nucleus, ventrolateral part;

[0109] LDDM, laterodorsal thalamic nucleus, dorsomedial part;

[0110] VPL, ventral posterolateral nucleus of the thalamus;

[0111] MGD, medial genicluate nucleus, dorsal part;

[0112] MGV, medial genicluate nucleus, ventral part;

[0113] DLG, dorsal lateral geniculate nucleus

[0114] dRt, vRt, dorsal and ventral parts of the reticular nucleus of the thalamus.

[0115] DLStr, dorsolateral striatum;

[0116] VMStr, ventromedial striatum;

[0117] SN, substantia nigra;

[0118] AcbC, nucleus accumbens core;

[0119] AcbS, nucleus accumbens shell;

[0120] MM, mammillary body;

[0121] MG, medial geniculates.

[0122] The decrease in Kv3.1 α-subunit mRNA expression observed in these studies parallel the selective changes previously observed in parvalbumin mRNA expression within the prelimbic cortex and the reticular nucleus of the thalamus. Moreover, the PCP-induced decreases in Kv3.1 α-subunit mRNA expression were reversed by chronic co-administration of Y-931 and olanzapine, as were PCP-induced changes in parvalbumin mRNA expression. Since parvalbumin expression is altered within the prefrontal cortex of schizophrenic patients and in rats after treatment with chronic PCP, these data suggest that Kv3.1 α-subunit mRNA may also be altered within schizophrenia in a similar manner.

[0123] As the chronic model of schizophrenia also produces an increase in Kv3.2 and Kv3.3 mRNA expression in the rat, these data suggest that Kv3.2 and Kv3.3 mRNA may also be altered in schizophrenia.

[0124] Drugs acting at the Kv3 channels have potential therapeutic roles in Schizophrenia. The hypothesis is that the decrease in Kv3.1 mRNA may affect the firing activity of the GABAergic interneurons in which it is located, which further contributes to an imbalance between the excitatory (glutamatergic) and inhibitory (GABAergic) pathways within the prefrontal cortex (which may be linked to negative symptoms and cognitive dysfunction). The changes in Kv3.2 mRNA suggest that thalamic relay neurons may also be mis-firing, which again may contribute to an imbalance between the excitatory (glutamatergic) and inhibitory (GABAergic) pathways within the prefrontal cortex. The changes in Kv3.3 mRNA may also disrupt the balance between the excitatory (glutamatergic) and inhibitory (GABAergic) pathways within the prefrontal cortex.

[0125] A drug which can restore Kv3.1, Kv3.2 and Kv3.3 expression may restore GABAergic interneuron activity back to normal.

[0126] Kv3.1 may be a good marker for the screening of antipsychotic activity because of the reversal with the a typical antipsychotic olanzapine and Y-931 as shown in these data.

[0127] This application is based on application No.02007114.8 filed in EPC, the contents of which are incorporated hereinto by reference.

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 9 <210> SEQ ID NO 1 <211> LENGTH: 3977 <212> TYPE: DNA <213> ORGANISM: Rattus norvegicus <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (1162)..(2919) <220> FEATURE: <221> NAME/KEY: gene <222> LOCATION: (1)..(3977) <220> FEATURE: <221> NAME/KEY: polyA_signal <222> LOCATION: (3958)..(3963) <300> PUBLICATION INFORMATION: <301> AUTHORS: Luneau,C.J., Williams,J.B., Marshall,J., Levitan,E.S., Oliva,C., Smith,J.S., Antanavage,J., Folander,K., Stein,R.B., Swanson,R., Kaczmarek,L.K. and Buhrow,S.A. <302> TITLE: Alternate splicing contributes to K+ channel diversity in the mammalian central nervous system. <303> JOURNAL: Proc. Natl. Acad. Sci. USA. <304> VOLUME: 88 <305> ISSUE: 5 <306> PAGES: 3932-3936 <308> DATABASE ACCESSION NUMBER: NM_012856 <309> DATABASE ENTRY DATE: 1991-05-01 <400> SEQUENCE: 1 gaacgagcaa gcgagcaggc agcggagcag cagcccggag gcagcagcgg cggcggtggt 60 ggcggcagtg gccgctccgc gcctcgcctc cctggcctcg ccagcctcgt tgcgccgcgc 120 ccggacctgc cacccccgcc taccgggccc gacctcggca gcgcccctcg catcggctgc 180 cagcgccacc cgccctccca gagcagtgag cggagtgcgg ggcgcagaaa caccggagcc 240 agtgcccgcc agccccgcca agcaaaacgg gctgagagaa cctacgctcg gcccagcgcg 300 gctccacagc cgtccgggag ctgtcccttc agcaccgccg cggaagcctg agtcccagcg 360 cagcccagcg gaacccctga cccagcccga gcgcaccagg cgctgcgctt agcggcagcc 420 ccgcggggag cacccttgtg cccctaccca ggggacctgc catctcctcc gggaggcggg 480 gagaaggaac gaggagggag gtcgggcagc ttcacccgcc accgagggga gtaggcagac 540 aagcaaggag atccgaaggg gatcggtcac gcagggagga gagcaagccg catccgtccc 600 caccgcaccg ggagcgcgct gcggcgacca ccgcagagcc aagcgcggat ttctcgtaac 660 cccctctttc ctagcagggg ctggtctatc ggtccggccc ccgaaacgga gcagctgacc 720 ttcccctaaa aagctttgtg tcgatttctc catttttccc gctgagatgg taccgggagc 780 ccggcccccc catcatctct cccctcctcc cgggcctcgc cgctgagcgc cgccccactc 840 ccttcctccc tccctcttta cctccctcct ctcttccact gcctcctccg cagccaggcc 900 agctccctct cacactaggc gccttaaaga ccctaaggag cccgcgcaca cacccctgga 960 cccgcacctg actgacagct ccccctgagg gggcttggct cgttggttgg ggtgggtggc 1020 cagagccgcg gtcctctgtg ccccccgacg gctgggggga ggggggaaga ggccctgcgc 1080 ccccctcccc gtcgccaact ccccctggcg gcagctccca tgggtgtcgc tgggccgcgc 1140 catgcctaag ggggcgccgc g atg ggc caa ggg gac gag agc gag cgc atc 1191 Met Gly Gln Gly Asp Glu Ser Glu Arg Ile 1 5 10 gtg atc aac gtg ggc ggc acg cgc cac cag acg tac cgc tcg acg ctg 1239 Val Ile Asn Val Gly Gly Thr Arg His Gln Thr Tyr Arg Ser Thr Leu 15 20 25 cgc acg ctg ccc ggc acg cgg ctt gcc tgg ctg gcg gag ccg gac gcc 1287 Arg Thr Leu Pro Gly Thr Arg Leu Ala Trp Leu Ala Glu Pro Asp Ala 30 35 40 cac agc cac ttc gac tat gac ccg cgc gct gac gag ttc ttc ttc gac 1335 His Ser His Phe Asp Tyr Asp Pro Arg Ala Asp Glu Phe Phe Phe Asp 45 50 55 cgc cac ccg ggc gtc ttc gct cac atc ctg aac tat tac cgc acc ggc 1383 Arg His Pro Gly Val Phe Ala His Ile Leu Asn Tyr Tyr Arg Thr Gly 60 65 70 aag cta cac tgc ccg gcc gac gtg tgc ggg ccg ctc tac gag gag gag 1431 Lys Leu His Cys Pro Ala Asp Val Cys Gly Pro Leu Tyr Glu Glu Glu 75 80 85 90 ctg gcc ttc tgg ggc atc gac gag acg gac gtg gag ccc tgc tgc tgg 1479 Leu Ala Phe Trp Gly Ile Asp Glu Thr Asp Val Glu Pro Cys Cys Trp 95 100 105 atg acg tat cgc cag cac cgc gac gct gag gag gcg ctg gac agc ttt 1527 Met Thr Tyr Arg Gln His Arg Asp Ala Glu Glu Ala Leu Asp Ser Phe 110 115 120 ggt ggc gcg ccc ttg gac aac agc gcc gac gac gcg gac gcc gac ggc 1575 Gly Gly Ala Pro Leu Asp Asn Ser Ala Asp Asp Ala Asp Ala Asp Gly 125 130 135 ccc ggc gac tcg ggc gac ggc gag gac gag ctg gag atg acc aag aga 1623 Pro Gly Asp Ser Gly Asp Gly Glu Asp Glu Leu Glu Met Thr Lys Arg 140 145 150 ttg gcg ctc agt gac tcc cca gat ggc cgg cct ggc ggc ttc tgg cgc 1671 Leu Ala Leu Ser Asp Ser Pro Asp Gly Arg Pro Gly Gly Phe Trp Arg 155 160 165 170 cgc tgg cag cca cgc atc tgg gca ctg ttc gag gac ccc tac tca tcc 1719 Arg Trp Gln Pro Arg Ile Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser 175 180 185 cgc tat gcg cgg tac gtg gcc ttt gcc tcc ctc ttc ttc atc ctg gtc 1767 Arg Tyr Ala Arg Tyr Val Ala Phe Ala Ser Leu Phe Phe Ile Leu Val 190 195 200 tcc atc aca acc ttc tgt ctg gag acc cac gag cgc ttc aac ccc atc 1815 Ser Ile Thr Thr Phe Cys Leu Glu Thr His Glu Arg Phe Asn Pro Ile 205 210 215 gtg aac aag aca gaa att gag aac gtt cga aat ggc aca caa gtg cgg 1863 Val Asn Lys Thr Glu Ile Glu Asn Val Arg Asn Gly Thr Gln Val Arg 220 225 230 tac tac cgg gaa gcg gag acg gag gcc ttc ctc acc tac atc gag ggt 1911 Tyr Tyr Arg Glu Ala Glu Thr Glu Ala Phe Leu Thr Tyr Ile Glu Gly 235 240 245 250 gtc tgc gtg gtc tgg ttc acc ttc gag ttc ctc atg cgt gtt gtc ttc 1959 Val Cys Val Val Trp Phe Thr Phe Glu Phe Leu Met Arg Val Val Phe 255 260 265 tgt ccc aac aag gtg gag ttc atc aag aac tcc ctc aat atc att gac 2007 Cys Pro Asn Lys Val Glu Phe Ile Lys Asn Ser Leu Asn Ile Ile Asp 270 275 280 ttc gtg gcc atc ctc ccc ttc tac ctg gag gtg ggc cta agt ggc ctg 2055 Phe Val Ala Ile Leu Pro Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu 285 290 295 tcc tcc aaa gct gcc aag gac gtg cta ggc ttc ctg cgc gtc gtg cgc 2103 Ser Ser Lys Ala Ala Lys Asp Val Leu Gly Phe Leu Arg Val Val Arg 300 305 310 ttc gtg cgc atc ctc cgt atc ttc aag ctg acc cgc cat ttt gtg ggc 2151 Phe Val Arg Ile Leu Arg Ile Phe Lys Leu Thr Arg His Phe Val Gly 315 320 325 330 ctg cgg gtc ctg ggc cac acg ctc cgt gcc agc acc aac gag ttc ctg 2199 Leu Arg Val Leu Gly His Thr Leu Arg Ala Ser Thr Asn Glu Phe Leu 335 340 345 ctg ctt atc atc ttc ctg gcc ctg ggt gtg ctc atc ttt gcc acc atg 2247 Leu Leu Ile Ile Phe Leu Ala Leu Gly Val Leu Ile Phe Ala Thr Met 350 355 360 atc tac tat gct gag agg ata ggg gca cag ccc aat gac ccc agc gcc 2295 Ile Tyr Tyr Ala Glu Arg Ile Gly Ala Gln Pro Asn Asp Pro Ser Ala 365 370 375 agc gaa cac aca cac ttt aaa aat atc ccc atc ggc ttc tgg tgg gct 2343 Ser Glu His Thr His Phe Lys Asn Ile Pro Ile Gly Phe Trp Trp Ala 380 385 390 gtg gtc acc atg acg aca ctg ggc tat gga gac atg tat cct cag acg 2391 Val Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Tyr Pro Gln Thr 395 400 405 410 tgg tct ggg atg ttg gtg gga gca ctg tgc gcc ctg gct ggt gtg ctg 2439 Trp Ser Gly Met Leu Val Gly Ala Leu Cys Ala Leu Ala Gly Val Leu 415 420 425 acc att gcc atg ccg gtg ccc gtc atc gtg aac aat ttt ggg atg tac 2487 Thr Ile Ala Met Pro Val Pro Val Ile Val Asn Asn Phe Gly Met Tyr 430 435 440 tac tct tta gcc atg gct aag cag aaa cta cca aag aaa aaa aag aag 2535 Tyr Ser Leu Ala Met Ala Lys Gln Lys Leu Pro Lys Lys Lys Lys Lys 445 450 455 cat att ccg cgg cca cca cag ctg gga tct ccc aat tat tgt aaa tct 2583 His Ile Pro Arg Pro Pro Gln Leu Gly Ser Pro Asn Tyr Cys Lys Ser 460 465 470 gtc gta aac tct cca cac cac agt act cag agt gac aca tgt ccg ctg 2631 Val Val Asn Ser Pro His His Ser Thr Gln Ser Asp Thr Cys Pro Leu 475 480 485 490 gcc cag gaa gaa att tta gaa att aac aga gca gat tcc aaa ctg aat 2679 Ala Gln Glu Glu Ile Leu Glu Ile Asn Arg Ala Asp Ser Lys Leu Asn 495 500 505 ggg gag gtg gcg aag gcc gcg ctg gcg aac gaa gac tgc ccc cac ata 2727 Gly Glu Val Ala Lys Ala Ala Leu Ala Asn Glu Asp Cys Pro His Ile 510 515 520 gac cag gcc ctc act ccc gat gag ggc ctg ccc ttt acc cgc tcg ggc 2775 Asp Gln Ala Leu Thr Pro Asp Glu Gly Leu Pro Phe Thr Arg Ser Gly 525 530 535 acc cgc gag aga tac gga ccc tgc ttc ctc tta tca acc ggg gag tac 2823 Thr Arg Glu Arg Tyr Gly Pro Cys Phe Leu Leu Ser Thr Gly Glu Tyr 540 545 550 gcg tgc ccg cct ggt gga gga atg aga aag gat ctt tgc aaa gaa agc 2871 Ala Cys Pro Pro Gly Gly Gly Met Arg Lys Asp Leu Cys Lys Glu Ser 555 560 565 570 cct gtc att gct aag tat atg ccg aca gag gct gtg aga gtg act tga 2919 Pro Val Ile Ala Lys Tyr Met Pro Thr Glu Ala Val Arg Val Thr 575 580 585 ccaggcggct tggccgagga cactggtggc tattaagcat ctgggtggac ctgcagcccc 2979 tcctcaccct cggacagagt aaattcacgc catgcaggtt tgccggacga gtccgagtgg 3039 ccccgggcat tgtactaaga cggacgtagc tttttctacg gcccacggta actgaccgta 3099 gaggattcgc ccttctttct tttgattttc tttttctttc tttttttttt ttttagaagt 3159 taccttttat ttggggaggg ggggtcaagg ggagccttag catgacttgc atgaagttaa 3219 acagaaaacc cagctaaacc aaccccacca gcccctgctg tgactgtatg ctcactctaa 3279 ccaccaccga gaaccagaga aaggcaagag tctcttattt cttccagcat tctttgacac 3339 gtagtgtcgg agtcaaactg tgacggcgct tggtagaacc ctgtacattt ccgggagtgg 3399 gtgcgggggg gggggggagg tcagggacta aggatggggc caggggagtg gattgctttt 3459 ttgtacacga gacccagagg aaaggtccca aaaaggcagt cagtcatcgg tcacattgac 3519 ctcaccttca tagctcacct ctcgctcgga aaaccaagaa ctatgctccg aataggattg 3579 tggaaattca cactgccacc ctcttccacc tccgtttggc atgcttgcga cccaatggac 3639 ctctccccaa gaccccgaca gcggctagtt taggtcaatt ctctcatctt ggtgtgtagc 3699 tccagtgtga ccaagtttca taacaaattg tttcatagtt acaccacatg gattttccaa 3759 tgtcatttta aagccaggat gtagagtccc tccagttcag gaccacccag aggggcgcct 3819 cccctccacc tttactaagg cgaaaaccga cactgtatgc aatttagtac ttcagagctc 3879 aaagaaaaaa aaaaaaagaa aaaaaaagaa aaaagaaaaa ctgcatgccc aatgttatgc 3939 aaagagattc gagcatgaaa taaattttgt aacatggt 3977 <210> SEQ ID NO 2 <211> LENGTH: 585 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 2 Met Gly Gln Gly Asp Glu Ser Glu Arg Ile Val Ile Asn Val Gly Gly 1 5 10 15 Thr Arg His Gln Thr Tyr Arg Ser Thr Leu Arg Thr Leu Pro Gly Thr 20 25 30 Arg Leu Ala Trp Leu Ala Glu Pro Asp Ala His Ser His Phe Asp Tyr 35 40 45 Asp Pro Arg Ala Asp Glu Phe Phe Phe Asp Arg His Pro Gly Val Phe 50 55 60 Ala His Ile Leu Asn Tyr Tyr Arg Thr Gly Lys Leu His Cys Pro Ala 65 70 75 80 Asp Val Cys Gly Pro Leu Tyr Glu Glu Glu Leu Ala Phe Trp Gly Ile 85 90 95 Asp Glu Thr Asp Val Glu Pro Cys Cys Trp Met Thr Tyr Arg Gln His 100 105 110 Arg Asp Ala Glu Glu Ala Leu Asp Ser Phe Gly Gly Ala Pro Leu Asp 115 120 125 Asn Ser Ala Asp Asp Ala Asp Ala Asp Gly Pro Gly Asp Ser Gly Asp 130 135 140 Gly Glu Asp Glu Leu Glu Met Thr Lys Arg Leu Ala Leu Ser Asp Ser 145 150 155 160 Pro Asp Gly Arg Pro Gly Gly Phe Trp Arg Arg Trp Gln Pro Arg Ile 165 170 175 Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser Arg Tyr Ala Arg Tyr Val 180 185 190 Ala Phe Ala Ser Leu Phe Phe Ile Leu Val Ser Ile Thr Thr Phe Cys 195 200 205 Leu Glu Thr His Glu Arg Phe Asn Pro Ile Val Asn Lys Thr Glu Ile 210 215 220 Glu Asn Val Arg Asn Gly Thr Gln Val Arg Tyr Tyr Arg Glu Ala Glu 225 230 235 240 Thr Glu Ala Phe Leu Thr Tyr Ile Glu Gly Val Cys Val Val Trp Phe 245 250 255 Thr Phe Glu Phe Leu Met Arg Val Val Phe Cys Pro Asn Lys Val Glu 260 265 270 Phe Ile Lys Asn Ser Leu Asn Ile Ile Asp Phe Val Ala Ile Leu Pro 275 280 285 Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser Ser Lys Ala Ala Lys 290 295 300 Asp Val Leu Gly Phe Leu Arg Val Val Arg Phe Val Arg Ile Leu Arg 305 310 315 320 Ile Phe Lys Leu Thr Arg His Phe Val Gly Leu Arg Val Leu Gly His 325 330 335 Thr Leu Arg Ala Ser Thr Asn Glu Phe Leu Leu Leu Ile Ile Phe Leu 340 345 350 Ala Leu Gly Val Leu Ile Phe Ala Thr Met Ile Tyr Tyr Ala Glu Arg 355 360 365 Ile Gly Ala Gln Pro Asn Asp Pro Ser Ala Ser Glu His Thr His Phe 370 375 380 Lys Asn Ile Pro Ile Gly Phe Trp Trp Ala Val Val Thr Met Thr Thr 385 390 395 400 Leu Gly Tyr Gly Asp Met Tyr Pro Gln Thr Trp Ser Gly Met Leu Val 405 410 415 Gly Ala Leu Cys Ala Leu Ala Gly Val Leu Thr Ile Ala Met Pro Val 420 425 430 Pro Val Ile Val Asn Asn Phe Gly Met Tyr Tyr Ser Leu Ala Met Ala 435 440 445 Lys Gln Lys Leu Pro Lys Lys Lys Lys Lys His Ile Pro Arg Pro Pro 450 455 460 Gln Leu Gly Ser Pro Asn Tyr Cys Lys Ser Val Val Asn Ser Pro His 465 470 475 480 His Ser Thr Gln Ser Asp Thr Cys Pro Leu Ala Gln Glu Glu Ile Leu 485 490 495 Glu Ile Asn Arg Ala Asp Ser Lys Leu Asn Gly Glu Val Ala Lys Ala 500 505 510 Ala Leu Ala Asn Glu Asp Cys Pro His Ile Asp Gln Ala Leu Thr Pro 515 520 525 Asp Glu Gly Leu Pro Phe Thr Arg Ser Gly Thr Arg Glu Arg Tyr Gly 530 535 540 Pro Cys Phe Leu Leu Ser Thr Gly Glu Tyr Ala Cys Pro Pro Gly Gly 545 550 555 560 Gly Met Arg Lys Asp Leu Cys Lys Glu Ser Pro Val Ile Ala Lys Tyr 565 570 575 Met Pro Thr Glu Ala Val Arg Val Thr 580 585 <210> SEQ ID NO 3 <211> LENGTH: 2441 <212> TYPE: DNA <213> ORGANISM: Rattus norvegicus <220> FEATURE: <221> NAME/KEY: gene <222> LOCATION: (1)..(2411) <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (37)..(1953) <300> PUBLICATION INFORMATION: <301> AUTHORS: McCormack,T., Vega-Saenz de Miera,E.C. and Rudy,B. <302> TITLE: Molecular cloning of a member of a third class of Shaker-family K+channel genes in mammals <303> JOURNAL: Proc. Natl. Acad. Sci. U.S.A. <304> VOLUME: 88 <305> ISSUE: 9 <308> DATABASE ACCESSION NUMBER: NM_139217 <309> DATABASE ENTRY DATE: 1991-05-01 <400> SEQUENCE: 3 gtgttcgcct tccctagtca tgtctgagcc acagag atg ggc aag atc gag aac 54 Met Gly Lys Ile Glu Asn 1 5 aac gag agg gtg atc ctc aat gtc gga ggc acc agg cac gaa acc tac 102 Asn Glu Arg Val Ile Leu Asn Val Gly Gly Thr Arg His Glu Thr Tyr 10 15 20 cgc agc act ctc aag acc ctt cct gga act cgc ctg gcc ctt ctc gcc 150 Arg Ser Thr Leu Lys Thr Leu Pro Gly Thr Arg Leu Ala Leu Leu Ala 25 30 35 tcc tct gaa cct cag ggc gac tgc ctg act gct gcg ggt gac aag ctg 198 Ser Ser Glu Pro Gln Gly Asp Cys Leu Thr Ala Ala Gly Asp Lys Leu 40 45 50 cag ccg ctg ccc cct ccg ctg tct cca ccg ccg cga ccg cct ccc ttg 246 Gln Pro Leu Pro Pro Pro Leu Ser Pro Pro Pro Arg Pro Pro Pro Leu 55 60 65 70 tcc cct gtc ccc agc ggc tgc ttc gag ggc ggc gca ggc aac tgc agt 294 Ser Pro Val Pro Ser Gly Cys Phe Glu Gly Gly Ala Gly Asn Cys Ser 75 80 85 tcg cac ggt ggc aat ggc agc gac cac cct ggg gga ggc cgc gaa ttc 342 Ser His Gly Gly Asn Gly Ser Asp His Pro Gly Gly Gly Arg Glu Phe 90 95 100 ttc ttc gat cgc cac cca gga gtc ttc gcc tat gtg ctc aac tac tac 390 Phe Phe Asp Arg His Pro Gly Val Phe Ala Tyr Val Leu Asn Tyr Tyr 105 110 115 cgc acg ggc aag ctg cac tgc ccc gcc gac gtg tgt gga ccg ctc ttc 438 Arg Thr Gly Lys Leu His Cys Pro Ala Asp Val Cys Gly Pro Leu Phe 120 125 130 gag gaa gag ctg gca ttc tgg ggc atc gat gag acc gac gtg gag ccc 486 Glu Glu Glu Leu Ala Phe Trp Gly Ile Asp Glu Thr Asp Val Glu Pro 135 140 145 150 tgc tgc tgg atg acc tac agg cag cac cgg gac gcg gag gag gcc ctg 534 Cys Cys Trp Met Thr Tyr Arg Gln His Arg Asp Ala Glu Glu Ala Leu 155 160 165 gat atc ttc gag aca ccc gac ctc atc gga ggc gac cct ggt gat gat 582 Asp Ile Phe Glu Thr Pro Asp Leu Ile Gly Gly Asp Pro Gly Asp Asp 170 175 180 gag gac cta ggg ggc aag aga ctg ggc att gag gat gct gcg ggg ctg 630 Glu Asp Leu Gly Gly Lys Arg Leu Gly Ile Glu Asp Ala Ala Gly Leu 185 190 195 gga gga ccc gat ggc aag tct ggc cgc tgg agg aag ctg cag cct cgc 678 Gly Gly Pro Asp Gly Lys Ser Gly Arg Trp Arg Lys Leu Gln Pro Arg 200 205 210 atg tgg gct ctc ttt gag gac ccc tat tca tcc aga gcc gct agg ttt 726 Met Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser Arg Ala Ala Arg Phe 215 220 225 230 att gct ttt gct tct ctg ttc ttc att ttg gtt tcc atc aca acc ttt 774 Ile Ala Phe Ala Ser Leu Phe Phe Ile Leu Val Ser Ile Thr Thr Phe 235 240 245 tgc ctg gag aca cac gaa gct ttc aat att gtt aaa aac aag aca gag 822 Cys Leu Glu Thr His Glu Ala Phe Asn Ile Val Lys Asn Lys Thr Glu 250 255 260 cca gtc atc aac ggc acc agc gct gtt ctc cag tat gaa atc gaa acg 870 Pro Val Ile Asn Gly Thr Ser Ala Val Leu Gln Tyr Glu Ile Glu Thr 265 270 275 gat cct gcc ttg aca tat gtg gaa gga gtg tgt gtg gtg tgg ttt act 918 Asp Pro Ala Leu Thr Tyr Val Glu Gly Val Cys Val Val Trp Phe Thr 280 285 290 ttt gaa ttt tta gtc cgt att gtt ttc tcg ccc aat aaa ctt gag ttc 966 Phe Glu Phe Leu Val Arg Ile Val Phe Ser Pro Asn Lys Leu Glu Phe 295 300 305 310 atc aaa aat cta ttg aac atc att gac ttt gtg gcc atc ctc ccc ttc 1014 Ile Lys Asn Leu Leu Asn Ile Ile Asp Phe Val Ala Ile Leu Pro Phe 315 320 325 tac tta gag gtg gga ctc agc ggg ctg tct tcc aaa gcg gct aaa gat 1062 Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser Ser Lys Ala Ala Lys Asp 330 335 340 gtg ctc ggc ttt ctc agg gtg gtt agg ttt gtg agg atc ctg aga atc 1110 Val Leu Gly Phe Leu Arg Val Val Arg Phe Val Arg Ile Leu Arg Ile 345 350 355 ttc aag ctt acc cgc cat ttc gta ggt ctg aga gtg ctc gga cac act 1158 Phe Lys Leu Thr Arg His Phe Val Gly Leu Arg Val Leu Gly His Thr 360 365 370 ctt cgt gcg agc acc aat gaa ttt ttg ttg ctg atc atc ttt ctg gct 1206 Leu Arg Ala Ser Thr Asn Glu Phe Leu Leu Leu Ile Ile Phe Leu Ala 375 380 385 390 ctg gga gtt ttg ata ttc gct acg atg atc tac tac gct gag cga gta 1254 Leu Gly Val Leu Ile Phe Ala Thr Met Ile Tyr Tyr Ala Glu Arg Val 395 400 405 ggg gct caa cct aat gat ccc tca gcg agt gag cac aca cag ttc aaa 1302 Gly Ala Gln Pro Asn Asp Pro Ser Ala Ser Glu His Thr Gln Phe Lys 410 415 420 aac atc ccc att ggt ttc tgg tgg gct gtg gtg acc atg act acc tta 1350 Asn Ile Pro Ile Gly Phe Trp Trp Ala Val Val Thr Met Thr Thr Leu 425 430 435 ggc tat ggg gat atg tac ccc caa aca tgg tca ggg atg ttg gtg ggg 1398 Gly Tyr Gly Asp Met Tyr Pro Gln Thr Trp Ser Gly Met Leu Val Gly 440 445 450 gcc ttg tgt gct ctg gct gga gtg ctg acc ata gct atg cct gtg ccc 1446 Ala Leu Cys Ala Leu Ala Gly Val Leu Thr Ile Ala Met Pro Val Pro 455 460 465 470 gtc att gtc aac aat ttt ggg atg tac tac tcc ttg gca atg gcg aag 1494 Val Ile Val Asn Asn Phe Gly Met Tyr Tyr Ser Leu Ala Met Ala Lys 475 480 485 cag aaa ctt cca aga aaa aga aag aag cac att cct cct gcc cct ctg 1542 Gln Lys Leu Pro Arg Lys Arg Lys Lys His Ile Pro Pro Ala Pro Leu 490 495 500 gca agc tca cct aca ttt tgc aag aca gaa tta aac atg gct tgt aac 1590 Ala Ser Ser Pro Thr Phe Cys Lys Thr Glu Leu Asn Met Ala Cys Asn 505 510 515 agt acc cag agt gac aca tgt ctg ggc aaa gaa aac cgg ctt ctg gaa 1638 Ser Thr Gln Ser Asp Thr Cys Leu Gly Lys Glu Asn Arg Leu Leu Glu 520 525 530 cat aac aga tca gtg tta tca ggt gac gac agt aca gga agt gag ccg 1686 His Asn Arg Ser Val Leu Ser Gly Asp Asp Ser Thr Gly Ser Glu Pro 535 540 545 550 cca tta tca cct ccg gaa agg ctc ccc atc aga cgc tct agt acc aga 1734 Pro Leu Ser Pro Pro Glu Arg Leu Pro Ile Arg Arg Ser Ser Thr Arg 555 560 565 gac aaa aac aga aga ggg gaa aca tgt ttc ctg ttg acg aca ggt gat 1782 Asp Lys Asn Arg Arg Gly Glu Thr Cys Phe Leu Leu Thr Thr Gly Asp 570 575 580 tac acg tgc gct tct gat gga gga atc agg aaa gga tat gaa aaa tcc 1830 Tyr Thr Cys Ala Ser Asp Gly Gly Ile Arg Lys Gly Tyr Glu Lys Ser 585 590 595 cga agc tta aac aac ata gcg ggc ttg gca ggc aat gct ctg aga ctc 1878 Arg Ser Leu Asn Asn Ile Ala Gly Leu Ala Gly Asn Ala Leu Arg Leu 600 605 610 tct cca gta aca tcc ccc tac aac tct ccg tgt cct ctg agg cgc tct 1926 Ser Pro Val Thr Ser Pro Tyr Asn Ser Pro Cys Pro Leu Arg Arg Ser 615 620 625 630 cgg tct ccc atc cca tct atc ttg taa accaaactgc accaatcggc 1973 Arg Ser Pro Ile Pro Ser Ile Leu 635 taaattctat cactacaact cctgtccacc ctgtactgga aacaattaac tatagagttt 2033 ctccaggctc cattaagaac agtgtagatc ctgcatgaca ttactattcg aagtcagaaa 2093 tgctactcga gtagctagaa catcttttcc tggctttaaa gatggcctaa agtagtgctg 2153 ctactcagta agagttgccc aatttccttt cgctatacgg tgaccaatag cgtcagatat 2213 tggccagtgc acgaatgcat aagcaaatct tcagggagat attctttaat agtgtgcttc 2273 taaatgccaa ccacttcact ggaccttcct ttcttgtgac tgactccaac ccattctgaa 2333 gatgtctggg atcctatcta gatcgtataa accatgactt tggtcagctc gtttgcatgg 2393 accatcttgc ctgtatcacc tgaatacagt gtgtagcgtc ctggtacc 2441 <210> SEQ ID NO 4 <211> LENGTH: 638 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 4 Met Gly Lys Ile Glu Asn Asn Glu Arg Val Ile Leu Asn Val Gly Gly 1 5 10 15 Thr Arg His Glu Thr Tyr Arg Ser Thr Leu Lys Thr Leu Pro Gly Thr 20 25 30 Arg Leu Ala Leu Leu Ala Ser Ser Glu Pro Gln Gly Asp Cys Leu Thr 35 40 45 Ala Ala Gly Asp Lys Leu Gln Pro Leu Pro Pro Pro Leu Ser Pro Pro 50 55 60 Pro Arg Pro Pro Pro Leu Ser Pro Val Pro Ser Gly Cys Phe Glu Gly 65 70 75 80 Gly Ala Gly Asn Cys Ser Ser His Gly Gly Asn Gly Ser Asp His Pro 85 90 95 Gly Gly Gly Arg Glu Phe Phe Phe Asp Arg His Pro Gly Val Phe Ala 100 105 110 Tyr Val Leu Asn Tyr Tyr Arg Thr Gly Lys Leu His Cys Pro Ala Asp 115 120 125 Val Cys Gly Pro Leu Phe Glu Glu Glu Leu Ala Phe Trp Gly Ile Asp 130 135 140 Glu Thr Asp Val Glu Pro Cys Cys Trp Met Thr Tyr Arg Gln His Arg 145 150 155 160 Asp Ala Glu Glu Ala Leu Asp Ile Phe Glu Thr Pro Asp Leu Ile Gly 165 170 175 Gly Asp Pro Gly Asp Asp Glu Asp Leu Gly Gly Lys Arg Leu Gly Ile 180 185 190 Glu Asp Ala Ala Gly Leu Gly Gly Pro Asp Gly Lys Ser Gly Arg Trp 195 200 205 Arg Lys Leu Gln Pro Arg Met Trp Ala Leu Phe Glu Asp Pro Tyr Ser 210 215 220 Ser Arg Ala Ala Arg Phe Ile Ala Phe Ala Ser Leu Phe Phe Ile Leu 225 230 235 240 Val Ser Ile Thr Thr Phe Cys Leu Glu Thr His Glu Ala Phe Asn Ile 245 250 255 Val Lys Asn Lys Thr Glu Pro Val Ile Asn Gly Thr Ser Ala Val Leu 260 265 270 Gln Tyr Glu Ile Glu Thr Asp Pro Ala Leu Thr Tyr Val Glu Gly Val 275 280 285 Cys Val Val Trp Phe Thr Phe Glu Phe Leu Val Arg Ile Val Phe Ser 290 295 300 Pro Asn Lys Leu Glu Phe Ile Lys Asn Leu Leu Asn Ile Ile Asp Phe 305 310 315 320 Val Ala Ile Leu Pro Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser 325 330 335 Ser Lys Ala Ala Lys Asp Val Leu Gly Phe Leu Arg Val Val Arg Phe 340 345 350 Val Arg Ile Leu Arg Ile Phe Lys Leu Thr Arg His Phe Val Gly Leu 355 360 365 Arg Val Leu Gly His Thr Leu Arg Ala Ser Thr Asn Glu Phe Leu Leu 370 375 380 Leu Ile Ile Phe Leu Ala Leu Gly Val Leu Ile Phe Ala Thr Met Ile 385 390 395 400 Tyr Tyr Ala Glu Arg Val Gly Ala Gln Pro Asn Asp Pro Ser Ala Ser 405 410 415 Glu His Thr Gln Phe Lys Asn Ile Pro Ile Gly Phe Trp Trp Ala Val 420 425 430 Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Tyr Pro Gln Thr Trp 435 440 445 Ser Gly Met Leu Val Gly Ala Leu Cys Ala Leu Ala Gly Val Leu Thr 450 455 460 Ile Ala Met Pro Val Pro Val Ile Val Asn Asn Phe Gly Met Tyr Tyr 465 470 475 480 Ser Leu Ala Met Ala Lys Gln Lys Leu Pro Arg Lys Arg Lys Lys His 485 490 495 Ile Pro Pro Ala Pro Leu Ala Ser Ser Pro Thr Phe Cys Lys Thr Glu 500 505 510 Leu Asn Met Ala Cys Asn Ser Thr Gln Ser Asp Thr Cys Leu Gly Lys 515 520 525 Glu Asn Arg Leu Leu Glu His Asn Arg Ser Val Leu Ser Gly Asp Asp 530 535 540 Ser Thr Gly Ser Glu Pro Pro Leu Ser Pro Pro Glu Arg Leu Pro Ile 545 550 555 560 Arg Arg Ser Ser Thr Arg Asp Lys Asn Arg Arg Gly Glu Thr Cys Phe 565 570 575 Leu Leu Thr Thr Gly Asp Tyr Thr Cys Ala Ser Asp Gly Gly Ile Arg 580 585 590 Lys Gly Tyr Glu Lys Ser Arg Ser Leu Asn Asn Ile Ala Gly Leu Ala 595 600 605 Gly Asn Ala Leu Arg Leu Ser Pro Val Thr Ser Pro Tyr Asn Ser Pro 610 615 620 Cys Pro Leu Arg Arg Ser Arg Ser Pro Ile Pro Ser Ile Leu 625 630 635 <210> SEQ ID NO 5 <211> LENGTH: 3410 <212> TYPE: DNA <213> ORGANISM: Rattus norvegicus <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (223)..(2262) <220> FEATURE: <221> NAME/KEY: gene <222> LOCATION: (1)..(3410) <300> PUBLICATION INFORMATION: <301> AUTHORS: Vega-Saenz de Miera,E., Moreno,H., Fruhling,D., Kentros, C. and Rudy,B. <302> TITLE: Cloning of ShIII (Shaw-like) cDNAs encoding a novel high-voltage-activating, TEA-sensitive, type-A K+ channel <303> JOURNAL: Proc. R. Soc. Lond., B, Biol. Sci. <304> VOLUME: 248 <305> ISSUE: 1321 <306> PAGES: 9-18 <308> DATABASE ACCESSION NUMBER: NM_053997 <309> DATABASE ENTRY DATE: 1991-05-01 <400> SEQUENCE: 5 aagctttttg tgcaatccca cctcctctag ctaggcttgg ttagagtctg cctagccgtg 60 gccccgccca ctccatcagt ccaatcagct cgtgttctcc ctccacctgc ccaatcactc 120 cctccccatc cattcatcgc ctcctcctgc ccaatcacat ctgcttctct accaaggctc 180 cgccccaaca ccctgccccc ctcagccccg cctccctgtc ca atg ctc agc tca 234 Met Leu Ser Ser 1 gtg tgc gtc tgg tcg ttc agc ggg cgc cag ggg acc cgc aag cag cat 282 Val Cys Val Trp Ser Phe Ser Gly Arg Gln Gly Thr Arg Lys Gln His 5 10 15 20 tct cag ccg gcg cca acg ccg cag ccg cct gag tcc tca ccg ccg cct 330 Ser Gln Pro Ala Pro Thr Pro Gln Pro Pro Glu Ser Ser Pro Pro Pro 25 30 35 ctg cta ccg ccg ccg cag cag cag tgc gct cag ccc ggc acc gcc gcc 378 Leu Leu Pro Pro Pro Gln Gln Gln Cys Ala Gln Pro Gly Thr Ala Ala 40 45 50 tcc ccg gcg ggt gcc ccg ctt tcc tgt ggg cct ggg ggc cgg cgc gcc 426 Ser Pro Ala Gly Ala Pro Leu Ser Cys Gly Pro Gly Gly Arg Arg Ala 55 60 65 gag cca tgc tcc ggg ctg ccg gcg gtg gcc atg ggg cgg cac ggc ggc 474 Glu Pro Cys Ser Gly Leu Pro Ala Val Ala Met Gly Arg His Gly Gly 70 75 80 ggc ggc ggc gac agc ggt aag atc gtg atc aac gtg ggc ggc gtg cgc 522 Gly Gly Gly Asp Ser Gly Lys Ile Val Ile Asn Val Gly Gly Val Arg 85 90 95 100 cat gag acg tac cgc tcc acg ttg cgc acc cta ccg ggg acc cgg ctg 570 His Glu Thr Tyr Arg Ser Thr Leu Arg Thr Leu Pro Gly Thr Arg Leu 105 110 115 gcc ggg ctg acc gag ccc gag gcg gcc gcg cgc ttt gac tac gac ccg 618 Ala Gly Leu Thr Glu Pro Glu Ala Ala Ala Arg Phe Asp Tyr Asp Pro 120 125 130 ggc acg gac gag ttc ttc ttt gac cgt cac ccg ggc gtc ttc gcc tac 666 Gly Thr Asp Glu Phe Phe Phe Asp Arg His Pro Gly Val Phe Ala Tyr 135 140 145 gtg ctc aac tac tac cgc acc ggc aag ctg cac tgc ccg gcc gac gtg 714 Val Leu Asn Tyr Tyr Arg Thr Gly Lys Leu His Cys Pro Ala Asp Val 150 155 160 tgc ggg ccg ctc ttc gag gag gag ctg ggc ttc tgg ggc ata gac gag 762 Cys Gly Pro Leu Phe Glu Glu Glu Leu Gly Phe Trp Gly Ile Asp Glu 165 170 175 180 acg gac gtg gag gcc tgc tgc tgg atg acc tac cgc cag cac cgt gat 810 Thr Asp Val Glu Ala Cys Cys Trp Met Thr Tyr Arg Gln His Arg Asp 185 190 195 gcc gaa gag gca ctg gac tcc ttc gag gct ccg gac tcc tcg ggc aac 858 Ala Glu Glu Ala Leu Asp Ser Phe Glu Ala Pro Asp Ser Ser Gly Asn 200 205 210 gcc aac gcc aac gcc gga ggc gcc cat gat gcg ggc ctg gac gac gag 906 Ala Asn Ala Asn Ala Gly Gly Ala His Asp Ala Gly Leu Asp Asp Glu 215 220 225 gcg ggc gca gga ggt ggc ggc ctg gac ggg gca ggc ggc gag ctc aag 954 Ala Gly Ala Gly Gly Gly Gly Leu Asp Gly Ala Gly Gly Glu Leu Lys 230 235 240 cgt ctg tgt ttt cag gac gcg ggc gga ggt gcc gga gga cct gcc gga 1002 Arg Leu Cys Phe Gln Asp Ala Gly Gly Gly Ala Gly Gly Pro Ala Gly 245 250 255 260 ggc ccg ggc ggc gcg ggc ggc acg tgg tgg agg cgc tgg cag ccc cgc 1050 Gly Pro Gly Gly Ala Gly Gly Thr Trp Trp Arg Arg Trp Gln Pro Arg 265 270 275 gtg tgg gcg ctt ttt gag gac ccc tac tcg tcg cgg gcc gcc agg tac 1098 Val Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser Arg Ala Ala Arg Tyr 280 285 290 gtg gcc ttc gcc tcc cta ttc ttt atc ctc atc tcc atc acc acc ttc 1146 Val Ala Phe Ala Ser Leu Phe Phe Ile Leu Ile Ser Ile Thr Thr Phe 295 300 305 tgc ctg gag aca cac gag ggc ttc atc cac atc agc aac aag acg gtg 1194 Cys Leu Glu Thr His Glu Gly Phe Ile His Ile Ser Asn Lys Thr Val 310 315 320 acg cag gcc tct cca atc cct ggg gct ccc ccg gag aat atc acc aat 1242 Thr Gln Ala Ser Pro Ile Pro Gly Ala Pro Pro Glu Asn Ile Thr Asn 325 330 335 340 gtg gag gtg gag acg gaa ccc ttt ttg acc tac gtg gaa ggc gtg tgt 1290 Val Glu Val Glu Thr Glu Pro Phe Leu Thr Tyr Val Glu Gly Val Cys 345 350 355 gtg gtc tgg ttc acc ttt gag ttt ctc atg cgg gtc acc ttc tgc ccg 1338 Val Val Trp Phe Thr Phe Glu Phe Leu Met Arg Val Thr Phe Cys Pro 360 365 370 gat aag gtg gag ttt ctc aaa agc agt ctt aac atc atc gac tgt gta 1386 Asp Lys Val Glu Phe Leu Lys Ser Ser Leu Asn Ile Ile Asp Cys Val 375 380 385 gcc atc ttg ccc ttc tac ttg gaa gtg ggc ctg tca ggt ctc agc tcc 1434 Ala Ile Leu Pro Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser Ser 390 395 400 aaa gct gcc aag gac gtg ctg ggc ttc ctg cgc gtc gtc cgc ttc gtg 1482 Lys Ala Ala Lys Asp Val Leu Gly Phe Leu Arg Val Val Arg Phe Val 405 410 415 420 cgc atc ctc cgt atc ttc aag ctg acc cgc cat ttt gtg ggc ctg cgg 1530 Arg Ile Leu Arg Ile Phe Lys Leu Thr Arg His Phe Val Gly Leu Arg 425 430 435 gtc ctg ggc cac acg ctc cgt gcc agc acc aac gag ttc ttg tta ctc 1578 Val Leu Gly His Thr Leu Arg Ala Ser Thr Asn Glu Phe Leu Leu Leu 440 445 450 att att ttc ctg gct ctg ggg gtc ctc atc ttt gcc acc atg atc tac 1626 Ile Ile Phe Leu Ala Leu Gly Val Leu Ile Phe Ala Thr Met Ile Tyr 455 460 465 tat gcc gag cgc atc ggg gcc gat cct gat gac atc ctg ggc tcc aac 1674 Tyr Ala Glu Arg Ile Gly Ala Asp Pro Asp Asp Ile Leu Gly Ser Asn 470 475 480 cac acc tac ttc aag aac atc ccc atc ggc ttc tgg tgg gct gtg gtc 1722 His Thr Tyr Phe Lys Asn Ile Pro Ile Gly Phe Trp Trp Ala Val Val 485 490 495 500 acc atg acc aca ctg ggc tat ggt gac atg tac ccc aag aca tgg tct 1770 Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Tyr Pro Lys Thr Trp Ser 505 510 515 ggg atg ctg gtc ggg gca ctg tgt gcc ctg gct ggt gtg ctg acc att 1818 Gly Met Leu Val Gly Ala Leu Cys Ala Leu Ala Gly Val Leu Thr Ile 520 525 530 gcc atg ccg gtg ccc gtc att gtc aac aac ttc ggc atg tac tat tca 1866 Ala Met Pro Val Pro Val Ile Val Asn Asn Phe Gly Met Tyr Tyr Ser 535 540 545 ctg gct atg gcc aag cag aaa ttg cca aag aag aaa aac aaa cat atc 1914 Leu Ala Met Ala Lys Gln Lys Leu Pro Lys Lys Lys Asn Lys His Ile 550 555 560 ccc agg ccc ccg cag cct ggc tca ccc aac tac tgc aag ccc gat ccc 1962 Pro Arg Pro Pro Gln Pro Gly Ser Pro Asn Tyr Cys Lys Pro Asp Pro 565 570 575 580 ccg cct ccg ccc cca cca cac ccc cac cac ggc agc ggt ggc atc agc 2010 Pro Pro Pro Pro Pro Pro His Pro His His Gly Ser Gly Gly Ile Ser 585 590 595 cca cca ccg ccc atc acc cct cct tcc atg ggg gtg act gtg gct ggg 2058 Pro Pro Pro Pro Ile Thr Pro Pro Ser Met Gly Val Thr Val Ala Gly 600 605 610 gct tac cca cct gga ccc cac acg cac ccc ggg ctg ctt agg ggt ggt 2106 Ala Tyr Pro Pro Gly Pro His Thr His Pro Gly Leu Leu Arg Gly Gly 615 620 625 gct ggg gga ctg gga att atg gga ttg cct cct ctg cca gcc cct ggt 2154 Ala Gly Gly Leu Gly Ile Met Gly Leu Pro Pro Leu Pro Ala Pro Gly 630 635 640 gag ccc tgc cca ctg gct caa gaa gag gtg att gaa acc aac agg gca 2202 Glu Pro Cys Pro Leu Ala Gln Glu Glu Val Ile Glu Thr Asn Arg Ala 645 650 655 660 ggt gag gct gga gcc agg act gga ggt gtg gga aga cct ggg ggt tgg 2250 Gly Glu Ala Gly Ala Arg Thr Gly Gly Val Gly Arg Pro Gly Gly Trp 665 670 675 ggg tcg ggg tag ggggaggagg cggcagggtt ggaggggatg cagaggcagg 2302 Gly Ser Gly atttctctta ggttcaggct gagcagagtg gaaggcaaca gggcagacag aagggacaag 2362 tggctagaag gctggagagg aggcacaagg agccacagaa accggattcc gtgtacaaga 2422 gagtgtgtga acatggattt cagccaggct gctctgaaag gcccctggtc agaagcagca 2482 cagtgagggt ctttggagaa gagactcaga aacccaggtg tgatggtgca tgcctccctt 2542 cctttgaagg tacttggtac ctcacatact tgggagatag aagtaggagg atgacgagtt 2602 caaggctagc ctgggtgaca tgtccctgtc tcaaaaatca tgggagaaaa aaatgaaaga 2662 gaaagaaagg aaagaggttg ggaggggtag gggagaaaga gaaaggcttg gtggcactct 2722 cctatagttc caacactggg gagactgagg caggagggtc aacacgtgtt ttgaggctat 2782 cctgggctac atacacagaa acaaaaggtc tgagtagctt cctgggggct gctagttcac 2842 accgattctt agggatattc ctatttctct atgagaaggc aagggaagac agggagagat 2902 agaaaggaaa aagggaaagg aatgagagcc acgtatggta atcctaaaat ggaggaggat 2962 caggagttca aggccggtgt cagctacgtg agaccctgtc tcagaaagaa aggggctcct 3022 gtaaagcaca ggaagtcgcg cgtgactcct ggcaaggcta gaggcaggtc tggctactgt 3082 cactttgtga ctgtggccgg tagtcctgag agccagagct ggggaatgta agtcacttaa 3142 ggagagaggg agaatggagt caggctgcca ggagggtcga ggtggaccct cgtaaaggaa 3202 ggcaaaaggg aggaacagac caaggccagc atcagggtgc ggagctgcca ggcagggtct 3262 gcacagggca gcaggaggca ctagggatcc cagagagttc ttgtaagaga agaggcagcc 3322 aggactggtt gaacgtacct gttatcccag gatttgggaa gctgaggcag aaggacagtt 3382 aagttcagag ctagcctgga ctatagag 3410 <210> SEQ ID NO 6 <211> LENGTH: 679 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 6 Met Leu Ser Ser Val Cys Val Trp Ser Phe Ser Gly Arg Gln Gly Thr 1 5 10 15 Arg Lys Gln His Ser Gln Pro Ala Pro Thr Pro Gln Pro Pro Glu Ser 20 25 30 Ser Pro Pro Pro Leu Leu Pro Pro Pro Gln Gln Gln Cys Ala Gln Pro 35 40 45 Gly Thr Ala Ala Ser Pro Ala Gly Ala Pro Leu Ser Cys Gly Pro Gly 50 55 60 Gly Arg Arg Ala Glu Pro Cys Ser Gly Leu Pro Ala Val Ala Met Gly 65 70 75 80 Arg His Gly Gly Gly Gly Gly Asp Ser Gly Lys Ile Val Ile Asn Val 85 90 95 Gly Gly Val Arg His Glu Thr Tyr Arg Ser Thr Leu Arg Thr Leu Pro 100 105 110 Gly Thr Arg Leu Ala Gly Leu Thr Glu Pro Glu Ala Ala Ala Arg Phe 115 120 125 Asp Tyr Asp Pro Gly Thr Asp Glu Phe Phe Phe Asp Arg His Pro Gly 130 135 140 Val Phe Ala Tyr Val Leu Asn Tyr Tyr Arg Thr Gly Lys Leu His Cys 145 150 155 160 Pro Ala Asp Val Cys Gly Pro Leu Phe Glu Glu Glu Leu Gly Phe Trp 165 170 175 Gly Ile Asp Glu Thr Asp Val Glu Ala Cys Cys Trp Met Thr Tyr Arg 180 185 190 Gln His Arg Asp Ala Glu Glu Ala Leu Asp Ser Phe Glu Ala Pro Asp 195 200 205 Ser Ser Gly Asn Ala Asn Ala Asn Ala Gly Gly Ala His Asp Ala Gly 210 215 220 Leu Asp Asp Glu Ala Gly Ala Gly Gly Gly Gly Leu Asp Gly Ala Gly 225 230 235 240 Gly Glu Leu Lys Arg Leu Cys Phe Gln Asp Ala Gly Gly Gly Ala Gly 245 250 255 Gly Pro Ala Gly Gly Pro Gly Gly Ala Gly Gly Thr Trp Trp Arg Arg 260 265 270 Trp Gln Pro Arg Val Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser Arg 275 280 285 Ala Ala Arg Tyr Val Ala Phe Ala Ser Leu Phe Phe Ile Leu Ile Ser 290 295 300 Ile Thr Thr Phe Cys Leu Glu Thr His Glu Gly Phe Ile His Ile Ser 305 310 315 320 Asn Lys Thr Val Thr Gln Ala Ser Pro Ile Pro Gly Ala Pro Pro Glu 325 330 335 Asn Ile Thr Asn Val Glu Val Glu Thr Glu Pro Phe Leu Thr Tyr Val 340 345 350 Glu Gly Val Cys Val Val Trp Phe Thr Phe Glu Phe Leu Met Arg Val 355 360 365 Thr Phe Cys Pro Asp Lys Val Glu Phe Leu Lys Ser Ser Leu Asn Ile 370 375 380 Ile Asp Cys Val Ala Ile Leu Pro Phe Tyr Leu Glu Val Gly Leu Ser 385 390 395 400 Gly Leu Ser Ser Lys Ala Ala Lys Asp Val Leu Gly Phe Leu Arg Val 405 410 415 Val Arg Phe Val Arg Ile Leu Arg Ile Phe Lys Leu Thr Arg His Phe 420 425 430 Val Gly Leu Arg Val Leu Gly His Thr Leu Arg Ala Ser Thr Asn Glu 435 440 445 Phe Leu Leu Leu Ile Ile Phe Leu Ala Leu Gly Val Leu Ile Phe Ala 450 455 460 Thr Met Ile Tyr Tyr Ala Glu Arg Ile Gly Ala Asp Pro Asp Asp Ile 465 470 475 480 Leu Gly Ser Asn His Thr Tyr Phe Lys Asn Ile Pro Ile Gly Phe Trp 485 490 495 Trp Ala Val Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Tyr Pro 500 505 510 Lys Thr Trp Ser Gly Met Leu Val Gly Ala Leu Cys Ala Leu Ala Gly 515 520 525 Val Leu Thr Ile Ala Met Pro Val Pro Val Ile Val Asn Asn Phe Gly 530 535 540 Met Tyr Tyr Ser Leu Ala Met Ala Lys Gln Lys Leu Pro Lys Lys Lys 545 550 555 560 Asn Lys His Ile Pro Arg Pro Pro Gln Pro Gly Ser Pro Asn Tyr Cys 565 570 575 Lys Pro Asp Pro Pro Pro Pro Pro Pro Pro His Pro His His Gly Ser 580 585 590 Gly Gly Ile Ser Pro Pro Pro Pro Ile Thr Pro Pro Ser Met Gly Val 595 600 605 Thr Val Ala Gly Ala Tyr Pro Pro Gly Pro His Thr His Pro Gly Leu 610 615 620 Leu Arg Gly Gly Ala Gly Gly Leu Gly Ile Met Gly Leu Pro Pro Leu 625 630 635 640 Pro Ala Pro Gly Glu Pro Cys Pro Leu Ala Gln Glu Glu Val Ile Glu 645 650 655 Thr Asn Arg Ala Gly Glu Ala Gly Ala Arg Thr Gly Gly Val Gly Arg 660 665 670 Pro Gly Gly Trp Gly Ser Gly 675 <210> SEQ ID NO 7 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide (45mer) used for in situ hybridization for the Kv3.1 alpha-subunit mRNA <400> SEQUENCE: 7 atagtcgaag tggctgtggg cgtccggctc cgccagccag gcaag 45 <210> SEQ ID NO 8 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide (45mer) used for in situ hybridization for Kv3.2 mRNA <400> SEQUENCE: 8 cacatcttta gccgctttgg aagacagccc gctgagtccc acctc 45 <210> SEQ ID NO 9 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide (45mer) used for in situ hybridization for Kv3.3 mRNA <400> SEQUENCE: 9 agaatgctgc ttgcgggtcc cctggcgccc gctgaacgac cagac 45 

1. A method for diagnosing schizophrenia, which comprises use of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5, a fragment thereof, and a polynucleotide having a sequence complementary to such sequence, as an index of schizophrenia.
 2. The method of claims 1, wherein the at least one kind of polynucleotide is selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5 and a polynucleotide having a sequence complementary to such sequence.
 3. The method of claim 1, wherein the at least one kind of polynucleotide is a polynucleotide having SEQ ID NO:1.
 4. A method for diagnosing schizophrenia, which comprises use of at least one kind of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3, a polypeptide encoded by the polynucleotide of SEQ ID NO:5, and a fragment thereof, as an index of schizophrenia.
 5. The method of claim 4, wherein the at least one kind of polypeptide is selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3 and a polypeptide encoded by the polynucleotide of SEQ ID NO:5.
 6. The method of claim 4, wherein the at least one kind of polypeptide is a polypeptide encoded by the polynucleotide of SEQ ID NO:1.
 7. A method for identifying a compound modulating the activity of Kv3 channels, which comprises analyzing an expression of Kv3 channel using at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5, a fragment thereof and a polynucleotide having a sequence complementary to such sequence.
 8. The method of claim 7, wherein the expression of Kv3 channel is analyzed using at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5 and a polynucleotide having a sequence complementary to such sequence.
 9. The method of claim 7, wherein the expression of Kv3 channel is analyzed using a polynucleotide having SEQ ID NO:1.
 10. A method for identifying a compound modulating the activity of Kv3 channels, which comprises analyzing an expression of Kv3 channel using at least one kind of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3, a polypeptide encoded by the polynucleotide of SEQ ID NO:5, and a fragment thereof. 11 The method of claim 10, wherein the expression of Kv3 channels is analyzed using at least one kind of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3, and a polypeptide encoded by the polynucleotide of SEQ ID NO:5.
 12. The method of claim 10, wherein the expression of Kv3 channel is analyzed using a polypeptide encoded by the polynucleotide of SEQ ID NO:1.
 13. A method for screening a compound regulating the expression of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, which comprises the steps of (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide, which is at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5 and a fragment thereof, and whose expression is desired to be controlled; (b) detecting the expression of polypeptide encoded by the polynucleotide in the cell; and (c) determining a compound promoting or suppressing the expression of the polypeptide as compared to a control (administration of vehicle alone).
 14. A method for screening a compound regulating the expression of a polynucleotide having SEQ ID NO:1, which comprises the steps of: (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of a polynucleotide having SEQ ID NO:1); (b) detecting the expression of polypeptide encoded by the polynucleotide in the cell; and (c) determining a compound promoting or suppressing the expression of the polypeptide as compared to a control (administration of vehicle alone).
 15. A method for screening a compound regulating the expression of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, which comprises the steps of: (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide, which is at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, and a polynucleotide having SEQ ID NO:5, and whose expression is desired to be controlled); (b) detecting the expression of polynucleotide in the cell; and (c) determining a compound promoting or suppressing the expression of the polynucleotide as compared to a control (administration of vehicle alone).
 16. A method for screening a compound regulating the expression of a polynucleotide having SEQ ID NO:1, which comprises the steps of: (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide having SEQ ID NO:1); (b) detecting the expression of polynucleotide in the cell; and (c) determining a compound promoting or suppressing the expression of the polynucleotide as compared to a control (administration of vehicle alone). 